1. Intravenous Steroid Treatment

   1. Aetna considers intravenous steroid therapy medically necessary for either of the following indications:

      1. Treatment of acute exacerbations of multiple sclerosis when the acute relapse is characterized by functionally disabling symptoms with documented evidence of neurological impairment (persons who have previously responded in a relapse phase are more likely to do so in the future).

      2. Use of intermittent pulse dose corticosteroids as a maintenance treatment for multiple sclerosis to delay disease progression. In many cases, members can be treated in the outpatient setting.

   2. Aetna considers hospital admission for intravenous steroid therapy medically necessary for the treatment of an acute exacerbation of multiple sclerosis that results in any of the following severe neurological deficits:

      1. Acute fulminant multiple sclerosis characterized by headache, vomiting, convulsions and eventually coma, with severe compromise of functioning of the central nervous system; or
      2. Acute quadriplegia; or
      3. Acute pseudobulbar palsy; or
      4. Acute transverse myelitis (or Brown-Sequard syndrome) with loss of function below the level of a suspected lesion in the spinal cord; or
      5. Acute cerebral symptoms with severe loss of intellectual capacity; or
      6. Acute epileptic seizure(s); or

      7. Acute visual loss. 

      An inpatient stay may also be considered medically necessary for persons who have had previous complications from high dose intravenous steroids that justify an inpatient admission.

2. Outpatient Treatment

   1. Clinically isolated syndrome (CIS) suggestive of multiple sclerosis. Aetna considers Copaxone (glatiramer acetate injection) medically necessary for treatment of persons who have experienced a first clinical episode and have magnetic resonance imaging (MRI) features consistent with multiple sclerosis.

   2. Relapsing, remitting multiple sclerosis.  Aetna considers any of the following treatments medically necessary for treatment of relapsing, remitting multiple sclerosis (but not for treatment of chronic progressive multiple sclerosis):

      1. Betaseron (interferon beta-1b) (see CPB 404 - Interferons for selection criteria)
      2. Avonex (interferon beta-1a) (see CPB 404 - Interferons for selection criteria)
      3. Rebif (interferon beta-1a) (see CPB 404 - Interferons for selection criteria)
      4. Copaxone (glatiramer acetate, copolymer-1)
      5. Intravenous immune globulin (IVIG) when standard approaches (i.e., interferons) have failed, become intolerable, or are contraindicated (see CPB 206 - Intravenous Immunoglobulins (IVIG)).
      6. Tysabri (natalizumab), when standard approaches (i.e., interferons) have failed, become intolerable, or are contraindicated (see discussion below) (Note: Tysabri is indicated for relapsing forms of multiple sclerosis)
      7. Novantrone (mitoxantrone)
      8. Imuran (azathioprine)

      9. H.P. Acthar Gel, for exacerbations refractory to corticosteroids (see CPB 762 - Repository Corticotropin Injection (H.P. Acthar Gel)).

   3. Chronic progressive multiple sclerosis.  Aetna considers Novantrone (mitoxantrone)* medically necessary for clinically deteriorating persons with either relapsing remitting or chronic progressive forms of multiple sclerosis.

   *Note: Because of the potential for functional cardiac changes, the product labeling for Novantrone states that persons receiving Novantrone should  have their left ventricular ejection fraction (LVEF) evaluated by echocardiogram or MUGA prior to every dose.

3. Experimental and Investigational Interventions:

   Aetna considers the following interventions experimental and investigational for multiple sclerosis:

   • Alpha-interferon
   • Anti-T-cell monoclonal antibodies other than natalizumab (Tysabri, Antegren)
   • Anti-lymphocyte globulin
   • Cladribine (Leustatin, 2-CDA)
   • Cooling garment
   • Cyclophosphamide (Cytoxan)
   • Cyclosporine (Sandimmune)
   • Daclizumab (Zenapax)
   • Dietary interventions (e.g., gluten-free diets, low fat diets, linoleate supplementation to diet, and dietary regimens with polyunsaturated fatty acids)
   • Electronystagmography (in the absence of vertigo or balance disorder)
   • Erythropoesis stimulating agents (unless criteria are met in CPB 195 - Erythropoiesis Stimulating Agents)
   • Gamma-interferon
   • Hyperbaric oxygen
   • IL-2-toxin
   • Methotrexate
   • Naltrexone
   • Oral myelin (Myloral)
   • Otoacoustic emissions (in the absence of signs of hearing loss)
   • Photopheresis (also see CPB 241 Extracorporeal Photochemotherapy (Photopheresis))
   • Plasmapheresis (plasma exchange)
   • Procarin (transdermal histamine)
   • Pulsed magnetic field therapy
   • PUVA (psoralen ultraviolet light)
   • Stem cell transplantation (see also CPB 606 Stem Cell Transplant for Autoimmune Diseases)
   • Statins
   • T-cell receptor therapy
   • T-cell vaccination
   • Total lymphoid irradiation
   • Transforming growth factor (TGF)-beta
   • Tumor necrosis factor antagonists
   • Tympanometry (in the absence of hearing loss). 

4. Plasma Exchange

   Aetna considers plasma exchange experimental and investigational for the treatment of various stages of multiple sclerosis.  Its effectiveness for this indication has not been proven.  See also CPB 285 - Plasmapheresis/Plasma Exchange/Therapeutic Apheresis.

5. Neutralizing Antibodies Against Interferon Beta

   Aetna considers assays of neutralizing antibodies (NABs) against interferon beta (Betaseron) to be experimental and investigational. 

6. Natalizumab (Tysabri)

   Aetna considers natalizumab (Tysabri, Biogen-Idec, Cambridge, MA) medically necessary for persons with relapsing forms of multiple sclerosis who have not responded adequately, or cannot tolerate, other treatments for multiple sclerosis.

   Aetna considers natalizumab experimental and investigational for chronic progressive multiple sclerosis.

7. APOE Genotyping 

   Aetna considers APOE genotyping of individuals with multiple sclerosis as experimental and investigational.

See also CPB 751 - Natalizumab (Tysabri).

Multiple sclerosis (MS) is an acquired inflammatory disease characterized by the destruction of myelin sheaths with preservation of axons occurring in multiple anatomic sites in the brain and spinal cord. Its clinical course is variable and unpredictable and exact etiology is unknown, although data suggests that it is an autoimmune disease triggered by a viral infection in genetically susceptible individuals.

The clinical course of multiple sclerosis can be classified as exacerbating-remitting, acute progressive, or chronic progressive.  Classical exacerbating-remitting usually begins with the acute or subacute onset of focal neurologic signs and symptoms, typically evolving over 1 to 3 days, stabilizing for a few days, and then improve spontaneously, followed by an onset of new focal symptoms months or years later.  On rare occasions, multiple sclerosis has a relatively acute onset with a rapidly progressive course involving multiple areas of the nervous system simultaneously and leading to severe impairment and death within a few weeks or months.  In chronic progressive multiple sclerosis, the course is insidious and progressive from the onset, usually occurs in patients greater than 35 years of age, and presents as a chronic myelopathy with slowly or intermittent, progressive symptoms.  Neuromyelitis optica (Devic’s syndrome) is a clinical syndrome consisting of both optic neuritis and transverse myelitis, occurring simultaneously or separately by only a brief interval in a patient without prior evidence of multiple sclerosis.

Patients with multiple sclerosis initially present with sensory disturbances in one or more limbs, disturbances of balance and gait with ataxia, optic nerve dysfunction with visual loss in one eye, diplopia, nystagmus, dysarthria, upper motor neuron spastic weakness, intention tremors, autonomic dysfunction, bladder dysfunction, spastic paraparesis, and retrobulbar neuritis, in various combinations. About 50% of patients with isolated optic neuritis will develop multiple sclerosis.

The diagnosis of multiple sclerosis remains clinical at present, with demonstration of signs and symptoms spread out in time and space being required.  Most patients have initial symptoms which totally resolve only to relapse with progressive residual disability after each exacerbation and significant neurologic dysfunction developing over a period of several years.  Less than one third of multiple sclerosis patients have a very benign course with minimal or no disability, and about 10% have a very malignant course with severe disability within months to a few years.

At onset, about 65% of patients have a relapsing-remitting form of the disease.  These patients have exacerbations with symptoms attributable to CNS lesions or plaques.  The flare-ups usually develop subacutely and resolve over weeks to months.  About 15% of patients have exacerbations similar to the relapsing-remitting disease but less complete recovery that leaves the patients with significant residual disability.  This form is referred to as the relapsing-progressive form.  Finally, there is the chronic progressive form dominated by spinal cord and cerebellar dysfunction.  In about 20% of patients, the initial symptoms start with this chronic progressive form, whereas, more often, it develops  out of the relapsing-remitting disorder over time.

The inflammatory response in the CNS consists predominantly of activated T lymphocytes and macrophages accompanied by a local immune reaction with the secretion of cytokines and the synthesis of oligoclonal immunoglobulin within the CNS.  Multiple sclerosis is thought to either be a cell-mediated autoimmune attack against myelin antigens or the presence of a persistent virus or infectious process within the CNS against which the inflammatory response is directed.

Many scattered, discrete areas of demyelination, termed plaques, are the pathologic hallmark of multiple sclerosis. Only limited regeneration of myelin occurs once the myelin sheath is destroyed (shadow plaques). Conduction of nerve impulses along axons denuded of their myelin is slowed or blocked.  This loss of conduction is analogous to a segment of electrical wire being stripped of its insulating cover, allowing escape of current and diminishment of its force down the rest of the wire.

The essentials of diagnosis are : episodic symptoms that may include sensory abnormalities, blurred vision, sphincter disturbances, and weakness with or without spasticity; patient is usually under 55 years of age at onset; single pathologic lesion cannot explain clinical findings; and multiple foci best demonstrated by MRI.

An accurate diagnosis is extremely important because this disorder mimics many diseases of the central nervous system.  The clinical history, including a history of at least 2 episodes of neurologic deficit, and physical examination showing objective clinical signs of lesions at more than one site within the CNS, remain of paramount importance in establishing a correct diagnosis.  However, the sine qua non of the initial diagnosis is the MRI demonstration that different regions of the white matter of the CNS have been affected by lesions at different times by demonstrating multiple white matter lesions (plaques) which represent a clearly defined patch of demyelination of sheaths of neurons in the CNS signifying areas of slowed or loss conduction leading to symptoms.  Diagnosis is confirmed with the aid of a number of pocedures. Cerebrospinal fluid (CSF) examination show elevated immunoglobulin G (IgG) and oligoclonal banding (electrophoretic bands which represents fractionations of IgG).  Evoked potential testing demonstrates conduction disturbances.  The diagnosis of multiple sclerosis rests as much as ever on the considered opinion of the neurologist, based heavily on the clinical features of the patient's illness. 

Intravenous steroids are safe and effective in treating acute exacerbations of multiple sclerosis.  Its use is directed at the early halting or diminishing of the destructive inflammatory process in the central nervous system, so that neurologic disability doesn't accumulate. For an acute relapse, a course of intravenous corticosteroids is typically given (500 mg to 1 gram of methylprednisolone (Solu-Medrol) over 30 to 60 minutes for 3 days).  This course can be extended up to 5 days (or to even 10 days) if the attack continues to progress or is slow in improving.  Intravenous methylprednisolone is also the usual primary treatment for optic neuritis.  The somewhat rapid effect of steroid treatment is based partly by reduction of white matter edema, and somewhat by an alteration of immunological factors. It is unusual in practice to give more than two or three courses of steroids for the treatment of relapses.

The treatment of multiple sclerosis must be individualized to the patient. Patients with stable disease, mild acute attacks, consisting of minor paresthesias, slight weakness, or incoordination that do not significantly interfere with normal activities require no treatment, as these attacks subside in 1 to 2 weeks without treatment.  Symptomatic treatment for spasticity, paresthesias, fatigue, and bowel and bladder difficulties may be required. Patients with progressive multiple sclerosis are treated with immunomodulating therapy, however, unfortunately no therapy has had a significant beneficial effect on the course of progressive multiple sclerosis.  Because the clinical examination is a relatively crude indicator to assess the efficacy of treatment, recent studies are using MRI to assess therapeutic benefit.

Early in the disease course, many patient exhibit little neurologic dysfunction and require minimal therapy. Many times their attacks are self-limiting and the main therapy offered is counsel and advise. When intervention is required, therapy is directed toward altering the clinical course with the use of immunosuppressives, or alleviating symptoms (spasticity, fatigue, depression, pain, bladder dysfunction, and cerebellar dysfunction).

An acute relapse of multiple sclerosis may require no treatment if it is mild or does not produce functional decline.  However, relapses that cause significant disability are usually treated with a course of intravenous corticosteroids.  Studies have shown that corticosteroids or ACTH decrease the length of a clinical relapse of multiple sclerosis, and some studies have shown that corticosteroids are superior to and have fewer side effects than ACTH.  It is not unusual to see the onset of a major depressive episode coincident with the first relapse episode, in spite of appropriate patient education as to the nature of the illness and in spite of mild severity of symptoms.  The response to steroids is often exhilarating (hypomanic, or even psychotic) followed by the return of severe depressive symptoms once the steroids are discontinued.  It is not unusual, therefore, that these patients may require a psychological assessment early on if depressive symptoms persist.

ACTH is secreted by the anterior pituitary and stimulates the adrenal cortex to secrete cortisol, aldosterone, and androgenic hormones. The anti-inflammatory, and possibly the inhibition of antibody production, appear to the effects most relevant to multiple sclerosis.  The growth of the use of synthetic glucocorticoids arose from efforts to minimize the many undesirable side effects related to aldosterone and androgen stimulation. Therefore, the use of oral glucocorticoids and the intravenous use of high-dose methylprednisolone has largely supplanted ACTH treatment.

Beta interferon (Betaseron) has been demonstrated in controlled trials to reduce the frequency and severity of acute attacks.  It has been shown to decrease the number of acute attacks of MS by about one-third and to decrease the average severity of attacks so that attacks classified as moderate to severe were reduced by more than 50%, as well as causing a dramatic reduction in the appearance of new lesions on MRI. 

As a result of the current thoughts on the immunological pathogenesis of the disease, immuno- suppressive and immnomodulating drugs remain the mainstay of treatment for progressive multiple sclerosis.  These drugs are used to prevent relapses and progression, to provide symptomatic treatment of multiple sclerosis, and occasionally for acute flare-ups. There are no large controlled trials of the efficacy of this therapy on acute exacerbations. The immunosuppressive agents currently used are all controversial, with data published supporting and disproving their efficacy. These therapies for acute flare-ups should be reserved for debilitating exacerbations, as patients appear to become resistant to therapy and there is no evidence that the ultimate degree of recovery is altered.  Furthermore, the National MS Society (2006) considered the use of cladribine (Leustatin) for MS to be controversial.  A Cochrane review (La Mantia et al, 2007) concluded that the overall effect of cyclophosphamide (administered as intensive schedule) in the treatment of progressive MS does not support its use in clinical practice.

Glatiramer acetate injection (Copaxone, Teva Pharmaceutical Industries Ltd., Jerusalem, Israel) has been approved by the U.S. Food and Drug Administration for the reduction of the frequency of relapses in relapsing remitting multiple sclerosis, including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. The FDA approved an expanded indication for glatiramer acetate injection to include the treatment of patients who have experienced a first clinical episode and have magnetic resonance imaging (MRI) features consistent with multiple sclerosis (MS).

Up to 85% of multiple sclerosis patients initially experience a single neurological event suggestive of MS, known as clinically isolated syndrome (CIS), and it has been demonstrated that early treatment initiation delays conversion from CIS to clinically definite MS (CDMS). The FDA granted approval after reviewing the results of the PreCISe study, which indicated time to development of a second exacerbation was significantly delayed in patients treated with glatiramer acetate injection compared to placebo (hazard ratio = 0.55; 95% confidence interval 0.40 to 0.77; p = 0.0005). The cumulative probability of developing the second attack during the three year study period was significantly lower in the glatiramer acetate injection group versus the placebo group (24.7% vs. 42.9%). The PreCISe study was a multinational, multi-center, prospective, double-blind, randomized, Phase III study that included 481 patients presenting with a single clinical episode and MRI scans suggestive of MS. Patients included were those who had a unifocal disease manifestation (i.e., clinical evidence of a single lesion). Patients received either glatiramer acetate 20mg/day or placebo as a subcutaneous injection and continued treatment for up to three years, unless a second exacerbation was experienced. Patients who experienced a second exacerbation continued the trial on active treatment for an additional two years. The primary efficacy outcome was time to development of second exacerbation. A pre-planned interim analysis was performed on data accumulated from 81 percent of the three-year placebo-controlled study exposure. The investigators reported that the 25th percentile of number of days to second exacerbation with glatiramer acetate injection increased from 336 days to 722 days compared with placebo (hazard ratio = 0.55; 95% confidence interval 0.40 to 0.77). In addition, the investigators reported that there was a significant reduction in the number of new T2 lesions and in the number of T1-enhancing lesions in the glatiramer acetate injection arm compared to the placebo arm, both at year one and year two magnetic resonance imaging (MRI) scans.

Novantrone (mitoxantrone for injection) acts in MS by suppressing the activity of T cells, B cells, and macrophages that are thought to lead the attack on the myelin sheath. Novantrone has been approved by the FDA for treatment of both the relapsing-remitting and chronic progressive forms of MS. Because of the potential for functional cardiac changes, the product labeling for Novantrone states that persons receiving Novantrone should have cardiac monitoring. The FDA recommends that the left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to every dose administered to patients with MS. Additional doses of Novantrone should not be administered to MS patients who have experienced either a drop in LVEF to below 50% or a clinically significant reduction in LVEF during Novantrone therapy. The labeling states that patients with MS should not receive a cumulative dose greater than 140mg/m2.

It is not known whether statins are effective therapy for multiple sclerosis. Birnbaum et al (2008) explored whether high-dose atorvastatin can be administered safely to persons with relapsing-remitting MS taking thrice-weekly, 44 microg dose subcutaneous interferon (IFN) beta-1a.  Subjects were randomized in a double-blind fashion to receive either placebo or atorvastatin at dosages of 40 or 80 mg/day for 6 months.  Blinded neurological examinations and brain MRI readings were obtained at months 0, 3, 6, and 9.  Laboratory blood testing was performed monthly.  Main outcome measures were the determination of drug toxicity using blood tests and ECG and determination of MS-related disease activity, either clinical relapses or new or contrast-enhancing lesions on MRI.  A total of 26 subjects received at least one dose of study drug.  Ten of 17 subjects on either 80 mg or 40 mg of atorvastatin per day had either new or enhancing T2 lesions on MRI or clinical relapses.  One of the 9 subjects on placebo had a relapse with active lesions on MRI.  Subjects receiving atorvastatin were at greater risk for either clinical or MRI disease activity compared to placebo (p = 0.019).  Significant changes in blood tests were noted only for lower cholesterol levels in subjects receiving atorvastatin.  The authors concluded that the combination of 40 or 80 mg atorvastatin with thrice-weekly, 44 microg IFN beta-1a in persons with MS resulted in increased MRI and clinical disease activity; caution is suggested in administering this combination.

In an editorial that accompanied the afore-mentioned article, Goldman and Cohen (2008) stated that "there are several ongoing larger studies of statins in MS, both as monotherapy and combined with other medications.  Hopefully these studies will clarify whether statins are useful as MS therapy".

Alleviation of the symptoms of multiple sclerosis becomes necessary, since effective curative therapy is not yet available.  Symptomatic treatment provides the means of improving the quality of life of individuals with MS.  Oral baclofen commonly is used to treat spasticity, however, a major side effect is increased weakness of the limb with possible negative effects on ambulation. Oral trizanidine can also be used to treat spasticity, where loss of strength appears to be less of a problem.  Intrathecal Baclofen via an implantable pump has been shown to be very effective in treating severe, intractable spasticity; however, careful selection of patients is mandatory as this is an invasive procedure with a number of potentially dangerous complications (hypotension, respiratory insufficiency, and meningitis).  When all forms of medical treatment are insufficient to prevent spasticity-related complications, injection of phenol can be used to perform neurolysis. Tenotomies of fixed contractures can also be useful in extremely disabled patients to allow adequate nursing. Oral clonazepam, hydroxyzine and beta-blockers can be used to treat tremors.  Irritative or obstructive bladder symptoms, as a result of spinal lesions causing detrusor hyperreflexia and incomplete bladder emptying, can be treated with oral anticholinergic medication (e.g., oxybutynin) and intermittent self-catheterization. Carbamazepine can be used to treat trigeminal neuralgia, the most common neurologic symptom in multiple sclerosis patients, and bouts of itching, burning sensations, twitching of the face, and a current of electricity flowing the length of their spine.

Hyperbaric oxygen (HBO) therapy has not been shown to be effective in the treatment of multiple sclerosis.  HBO therapy, the intermittent inhalation of 100% oxygen under a pressure greaterthan 1 atmospheres pressure (atm), is one of many unconventional treatments tried as a possible treatment for MS.  HBO can be administered in either a monoplace or multiplace chamber.  The latter accommodates 2 to 14 people and can achieve pressures up to 6 atm.  Patients breath 100% oxygen through a face mask, head hood, or endotracheal tube and can be cared for by medical personnel directly within the chamber.  Monoplace chambers treat a single patient in an environment maintained at 100% oxygen, thus, no mask is required.  Possible complications of HBO therapy include barotrauma (ear or sinus trauma, tympanic membrane rupture, pneumothorax, air embolism), oxygen toxicity (central nervous system or pulmonary), fire, reversible visual changes and claustrophobia.  Although early uncontrolled clinical trials and anecdotal reports suggested that hyperbaric oxygen therapy (HBO) may be beneficial in the management of multiple sclerosis, more recent controlled studies with larger sample sizes indicate that this modality is not effective in the treatment of this central nervous system disease.

Ehrenreich et al (2007) performed an investigator-driven, exploratory open label study (phase I/IIa) in patients with chronic progressive MS.  Main study objectives were (i) evaluating safety of long-term high-dose intravenous recombinant human erythropoietin (rhEPO) treatment in MS, and (ii) collecting first evidence of potential efficacy on clinical outcome parameters.  A total of 8 MS patients: 5 randomly assigned to high-dose (48,000 IU), 3 to low-dose (8000 IU) rhEPO treatment, and, as disease controls, 2 drug-naïve Parkinson patients (receiving 48,000 IU) were followed over up to 48 weeks: a 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase.  Clinical and electrophysiological improvement of motor function, reflected by a reduction in expanded disability status scale, and of cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for 3 to 6 months after cessation of EPO application.  In contrast, low-dose EPO MS patients and drug-naïve Parkinson patients did not improve in any of the parameters tested.  There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings.  The authors concluded that this first pilot study demonstrated the necessity and feasibility of controlled trials using high-dose rhEPO in chronic progressive MS.

In a phase II, double-blind, 48-week clinical trial involving 104 patients with relapsing–remitting MS, Hauser et al (2008) assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15.  The primary end point was the total count of gadolinium-enhancing lesions detected on MRI scans of the brain at weeks 12, 16, 20, and 24.  Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse.  As compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (p < 0.001) and of total new gadolinium-enhancing lesions over the same period (p < 0.001); and these results were sustained for 48 weeks (p < 0.001).  As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5 % versus 34.3 %, p = 0.02) and week 48 (20.3 % versus 40.0 %, p = 0.04).  More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups.  The authors concluded that a single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks.  However, the authors noted that this phase II study was not designed to evaluate long-term safety or to detect uncommon adverse events.  They stated that the safety and effectiveness of rituximab for the treatment of MS need to be validated by larger and longer-term controlled studies.  MacFarland (2008) noted that a phase II clinical trial leaves many questions unanswered including the duration of the treatment effect, the effect of progression of disability, and most importantly the types of adverse events that may occur at low frequency.  Issues of long-term safety of rituximab must still be addressed, given reports to the FDA of progressive multifocal leukoencephalopathy in patients with lupus who were treated with rituximab.

In a cross-sectional study (n = 15), Sheffler and colleagues (2008) examined if an ankle foot orthosis (AFO) would improve gait velocity and tasks of functional ambulation in patients with MS.  Subjects experienced dorsiflexion and eversion weakness, and had used a physician-prescribed AFO for more than 3 months.  Ambulation was evaluated (i) without an AFO and (ii) with an AFO.  Outcome measures were the Timed 25-Foot (T25-FW) Walk portion of the Multiple Sclerosis Functional Composite and the five trials (floor, carpet, up and go, obstacles, and stairs) of the Modified Emory Functional Ambulation Profile (mEFAP).  The mean timed differences on the T25-FW and the five components of the mEFAP between the AFO versus no device trials were not statistically significant.  The authors concluded that in MS subjects with dorsiflexion and eversion weakness, no statistically significant improvement was found performing timed tasks of functional ambulation with an AFO.

Plasma exchange has not been proven for the treatment of various stages of multiple sclerosis. Laboratory abnormalities are suggestive that MS is an immune-mediated disease; this is the rational basis of offering plasma exchange.  Specifically, it is hypothesized that humoral factors may be involved, as evidenced by the presence of antimyelin antibodies and non-antibody demyelinating factors in the sera of patients with MS and the presence of circulating autoantibodies.  The specific identity of these humoral factors has not yet been identified.  Further evidence supporting the use of PE has been its success in other autoimmune diseases. However, available clinical studies, including randomized controlled clinical trials, have not proven that plasma exchange is effective for multiple sclerosis. A systematic review of the literature on plasma exchange for multiple sclerosis (Nicholas & Chataway, 2006) concluded that there is "insufficient evidence to assess plasma exchange in people with acute relapses of multiple sclerosis."

Assays of neutralizing antibodies (NABs) against interferon beta (Betaseron) have not been proven to be useful in multiple sclerosis.  About one-third of individuals develop NABs against interferon beta.  A number of laboratories have developed assays for these NABs (e.g., MxA Assay (Berlex Laboratories), NabFeron (Athena Diagnostics)). However, according to the peer reviewed medical literature, the clinical utility of these assays has not been established.  Evidence-based guidelines on multiple sclerosis from the American Academy of Neurology (Goodin, et al., 2002) state: "The rate of neutralizing antibody (NAb) production is probably less with IFN-1a treatment than with IFN-1b treatment, and the presence of NAb may be associated with a reduction in clinical effectiveness of IFN treatment.  The existing data are, however, ambiguous in this regard, and the clinical utility of measuring NAb in an individual on IFN therapy is uncertain."

While the European Federation of Neurological Societies Task Force on anti-IFN-beta antibodies in multiple sclerosis (Sorensen et al, 2005) recommended that tests for the presence of NABs should be performed in all patients at 12 and 24 months of interferon beta therapy, the consensus statement from an international conference on the significance of NABs to interferon beta during treatment of MS (Hartung et al, 2005) stated that “an international standardized assay for NAb is needed; and all patients with MS who receive IFN-beta therapy should be evaluated for the presence of Nab.  Moreover, guidelines on how to manage NAb-positive patients should be developed to optimize IFN-beta therapy; these treatment guidelines should be based on the results of well-controlled clinical studies …. An international standardized assay will facilitate direct comparison of NAb titers amongst studies and will provide further information regarding the immunogenecity of the various types of IFN-beta products and how NAb impact clinical efficacy".

Antonelli and colleagues (2005) stated that “There is a lack of substantial information on the biological/immunological phenomenon of neutralising antibodies in vivo development.  Nevertheless, sufficient experimental data are available to provide a rationale for monitoring the presence of anti-IFN antibodies in patients treated with IFN beta.  A standardised quantitative assay to detect antibody to IFNs must be agreed.  Only when results can be compared, both in terms of the qualitative presence and quantitative measurement of antibodies, will it be possible to monitor fully the ability of antibodies to cause a relapse during treatment.  Although there is increasing evidence to indicate that the development of antibodies to IFN beta may be associated with a failure of the beneficial effects of the therapy, the use of the seropositivity for neutralising antibodies to IFN beta as the only surrogate marker for clinical and therapeutic decision-making is questionable”.  Also, guidelines on multiple sclerosis from the Association of British Neurologists (2001) stated that monitoring neutralizing antibodies for beta interferon is not necessary.

Noronha (2007) noted that an effect on relapse rates and imaging parameters was noted in patients who tested positive for NAbs, but disability measures were unaffected or showed a trend toward improvement.  Patients who developed NAbs during IFN-beta1a therapy tended to remain NAb+, whereas those who developed NAbs during IFN-beta1b therapy tended to revert to NAb- over time.  The author stated that the prevalence of NAbs in suboptimal responders does not support a causal relationship of suboptimal responses to the development of NAbs.  Thus, decisions to alter treatment should be rendered by clinicians based on the clinical state of the patient.

Natalizumab (Tysabri, Biogen-Idec, Cambridge, MA) is indicated for persons with relapsing forms of multiple sclerosis who have not responded adequately, or cannot tolerate, other treatments for multiple sclerosis. Tysabri was initially approved by the U.S. Food and Drug Administration (FDA) in November 2004, but was withdrawn from the market in February 2005, after three patients in the drug's clinical trials developed progressive multifocal leukoencephalopathy (PML). Two of the cases were fatal.

The FDA allowed a clinical trial of natalizumab to resume in February 2006, following a re-examination of the patients who had participated in the previous clinical trials, confirming that there were no additional cases of PML. To decrease the possibility of patients developing PML in the future, the manufacturer, Biogen-IDEC, submitted to the FDA a Risk Management Plan, called the TOUCH Prescribing Program, to ensure safe use of the product.  The FDA has determined that natalizumab can be made available under the TOUCH Prescribing Program with the following main features:

• The drug will only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies registered with the program.
• Natalizumab will only be administered to patients who are enrolled in the program.
• Prior to initiating the therapy, health care professionals are to obtain the patient's magnetic resonance imaging (MRI) scan to help differentiate potential future multiple sclerosis symptoms from PML.
• Patients on natalizumab are to be evaluated at 3 and 6 months after the first infusion and every 6 months after that, and their status will be reported regularly to the product’s manufacturer.

To date, seven cases of PML have been identified in users of natalizumab. The FDA has reviewed information pertaining to the most recent cases and continues to recommend that natalizumab monotherapy may confer a lower risk of PML than when natalizumab is used together with other immunomodulatory medications.

An assessment of natalizumab for multiple sclerosis by the American Academy of Neurology included the following recommendations. 

• Because of the possibility that natalizumab therapy may be responsible for the increased risk of PML [progressive multifocal leukoencephalopathy], it is recommended that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course. This recommendation is very similar to that of the U.S. Food and Drug Administration (FDA).
• Similarly, because combination therapy with IFN-beta and natalizumab may increase the risk of PML, it should not be used. There are also no data to support the use of natalizumab combined with other disease-modifying agents as compared to natalizumab alone. The use of natalizumab in combination with agents not inducing immune suppression should be reserved for properly controlled and monitored clinical trials.

Shi et al (2008) stated that while the role of apolipoprotein E (APOE) polymorphism has been well recognized in cognitive neurodegenerative disorders, its role in MS is less clear. Studies indicated that 40 % to 60 % of patients with MS have evidence of cognitive impairment. These researchers examined if there is an association between APOE epsilon 4 and cognitive deficits in MS. They performed a standardized battery of neuropsychological tests investigating the four cognitive domains commonly impaired in MS and assessed the association of the presence of APOE epsilon 4 with cognition in these patients. A strong association was found between the presence of APOE epsilon 4 and cognitive deficits in patients with MS, especially in the domains of learning and memory. This association was strongest in the youngest cohort (aged 31 to 40 years) of patients with MS. The authors concluded that APOE epsilon 4 is significantly associated with cognitive impairment in patients with MS. However, the modest effects do not justify APOE genotyping of patients with MS in clinical practice.

Guerrero et al (2008) evaluated if there is any correlation between APOE genotype and severity according to Multiple Sclerosis Severity Score (MSSS). This study included 82 patients with disease duration of at least 2 years. These investigators collected data concerning demographic and clinical variables including age of onset, disease duration, Expanded Disability Status Scale (EDSS) score and the total number of relapses. They determined the latency to EDSS scores of 4.0 and 6.0; calculated progression index (PI) and relapse rate (RR); and ascertained MSSS in the global MSSS table. The authors reproted that 4 patients heterozygous for the E2 allele and 16 for the E4 allele. No patient was homozygous for E2 or E4. RR (p = 0.017 with 95 % CI: 0.005 to 0.57) and PI (p = 0.016 with 95 % CI: 0.004 to 0.38) were significantly lower in E4 carriers. Multiple Sclerosis Severity Score was not associated with carriership of E2 or E4. The authors concluded that these findings show no effect of the APOE genotype on the severity of MS measured by MSSS, as a recently published meta-analysis has noticed. Thus, the data do not support a role for APOE in MS severity.